Home Cart 0 Sign in  
X

[ CAS No. 86477-09-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 86477-09-0
Chemical Structure| 86477-09-0
Chemical Structure| 86477-09-0
Structure of 86477-09-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 86477-09-0 ]

Related Doc. of [ 86477-09-0 ]

Alternatived Products of [ 86477-09-0 ]

Product Details of [ 86477-09-0 ]

CAS No. :86477-09-0 MDL No. :MFCD11975789
Formula : C9H12N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :MGGGSJRWNQFCLE-UHFFFAOYSA-N
M.W :180.20 Pubchem ID :12841166
Synonyms :

Calculated chemistry of [ 86477-09-0 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.56
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 47.23
TPSA : 44.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.04
Log Po/w (XLOGP3) : 1.15
Log Po/w (WLOGP) : 1.01
Log Po/w (MLOGP) : 0.98
Log Po/w (SILICOS-IT) : 1.22
Consensus Log Po/w : 1.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.77
Solubility : 3.07 mg/ml ; 0.017 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 3.84 mg/ml ; 0.0213 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.72
Solubility : 3.43 mg/ml ; 0.0191 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.36

Safety of [ 86477-09-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 86477-09-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 86477-09-0 ]
  • Downstream synthetic route of [ 86477-09-0 ]

[ 86477-09-0 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 98262-66-9 ]
  • [ 623-47-2 ]
  • [ 86477-10-3 ]
  • [ 86477-09-0 ]
YieldReaction ConditionsOperation in experiment
57% at 120 - 122℃; for 12 h; A solution of 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (13.5 g, 0.107 mole, crude, from example 4) and ethyl propiolate (15.8 g, 16.3 ml, 0.16 mole) in dry N,N-dimethylformamide (50 ml) is stirred and heated to 120-122° C. under a nitrogen atmosphere for a period of 12 hours. The reaction is monitored for completion by HPLC [Prodigy ODS3 4.6.x.150 mm column, with a 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02percent trifluoroacetic acid. Retention times under these conditions were: 2.6-2.7 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer) and 2.8-2.9 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the less polar, undesired isomer). The UV detector was set at 215 nm, because at 254 nm the two isomers absorbed very differently, and the undesired isomer was almost undetectable). The mixture is then evaporated to a dark syrup under oil pump vacuum using a bath temperature up to 50° C. The ratio of the esters in the dark syrup is determined by NMR, as 2.13 to 1 in favor of the desired ester, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. The dark syrup is diluted with toluene and the solution is applied to a column of silica gel (500 mL) prepacked in hexanes by washing onto the column with hexanes. Elution is with hexanes-ethyl acetate mixture (4:1) followed by hexanes-ethyl acetate (1:1). Fractions are monitored by HPLC (same conditions as above). Fractions that contained both esters are combined and chromatographed once more. Fractions containing only ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate are combined and concentrated to give 11 g (57percent) of the pure ester as white crystals, m. p. 41-43° C. Similarly, 6.5 g (33.7percent) of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate is obtained as white crystals, m.p. 35-37° C.
41% at 120 - 125℃; for 8 - 11 h; The 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (971 g, 7.70 mol, made as in example 2) and 1,2-diethoxyethane (DEE, 2913 mL) are charged to a multinecked 12 L round bottom flask, is equipped with a water cooled condenser, and purged with nitrogen. The stirred solution is heated to 120-125° C. under a nitrogen atmosphere and ethyl propiolate (971 g, 9.90 mol) is added dropwise over a period of 3 hours (carbon dioxide evolution). The reaction is held at 120-125° C. for about 5 hours until the conversion is >99percent (<1percent of residual 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide, by GC-MS analysis). The mixture is then concentrated under oil pump vacuum using a rotary evaporator with a bath temperature up to 70° C. to a residue. About 1.5 kg of toluene is then added to the residue and the mixture is concentrated once more. A dark oil is obtained [1218 g, 46.9percent strength, (HPLC) in 41percent (real yield of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide]. [TABLE-US-00001] Ratio of 2- Ylide, Ester to 3- Addition Hold 3, Product 2-Ester Ester Time Time starting Crude 2-Ester percent Yield by GC-MS Solvent Temp° C. (hours)* (hours)** (g) (g) Wt percent (crude to real) (Area percent) DEE 120-125 3 5 971 1218 46.9 41 58/42 DEE 120-125 3 6.2 1400 1988 48.2 47 60/37 DEE 120-125 3 8 827 1075 45.5 42 57/40 *Addition time is the time taken to add the reagent, ethyl propiolate. **Hold time is the time the reaction is allowed to run beyond the addition time. The total reaction time is the sum of the addition time and the hold time.
42 %Chromat. at 120 - 125℃; for 5 h; To 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium Ylide (29.3 g, 0.232 mol prepared as in example 2) and chlorobenzene (97.2 g) under a nitrogen atmosphere at 120-125° C. is added dropwise ethyl propiolate (29.3 g, 0.299 mol) over a period of about 2 hours (carbon dioxide evolution). The reaction is held for about 3 hours until the conversion is >99percent (<1percent residual according to GC-MS analysis). The GC-MS ratio of the desired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, to the undesired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate, is 59/41 The mixture is then washed with water (50 mL). The organic phase is concentrated under oil pump vacuum up to a bath temperature of about 70° C. to afford a residue as a dark oil [39.1 g, 45.3percent strength (HPLC) in ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, 42percent (real yield of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide)]. The oil is characterized by HPLC, NMR.
Reference: [1] Patent: US2004/242874, 2004, A1, . Location in patent: Page 13-14
[2] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 2, p. 169 - 175
[3] Patent: US2004/242874, 2004, A1, . Location in patent: Page 12-13
[4] Patent: US2004/242874, 2004, A1, . Location in patent: Page 13
[5] Organic Process Research and Development, 2006, vol. 10, # 4, p. 712 - 716
  • 2
  • [ 98262-66-9 ]
  • [ 623-47-2 ]
  • [ 86477-09-0 ]
Reference: [1] Patent: EP1241170, 2002, A2, . Location in patent: Page 47
  • 3
  • [ 86477-05-6 ]
  • [ 623-47-2 ]
  • [ 86477-10-3 ]
  • [ 86477-09-0 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 10, p. 1067 - 1070
[2] Tetrahedron Letters, 1983, vol. 24, # 10, p. 1067 - 1070
  • 4
  • [ 86477-09-0 ]
  • [ 796729-03-8 ]
YieldReaction ConditionsOperation in experiment
57% With water; sodium hydroxide In 1,4-dioxane at 65℃; for 2.5 h; Example 162a
5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic Acid 162a
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (540 mg, 3.0 mmol), 2N Aqueous sodium hydroxide solution (3.5 mL), and 1,4-dioxane (3.0 mL).
The system was heated at 65° C. for 2.5 h.
It was then cooled to room temperature and adjusted the pH to 2-3 with concentrated HCl.
The solid was collected by filtration to afford 162a (260 mg, 57percent) as a yellow solid. MS-ESI: [M+H]+ 153.3
Reference: [1] Patent: US2013/116246, 2013, A1, . Location in patent: Paragraph 0581
[2] Patent: EP1241170, 2002, A2, . Location in patent: Page 59
  • 5
  • [ 86477-10-3 ]
  • [ 86477-09-0 ]
  • [ 796729-03-8 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With potassium hydroxide In ethanol at 10 - 26℃; for 4.2 - 5.5 h;
Stage #2: With hydrogenchloride In water
A freshly prepared solution of potassium hydroxide (87.6percent w/w pellets, 307.6 g, 4.80 mol) in 2B ethanol (absolute, 1862 mL) is added over a period of 1 hour to a stirred solution of 1063.6 g [46.5percent strength (HPLC), 2.744 mol real)] of the ester mixture [(from example 5), ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate) and ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate] in 2B ethanol (absolute, 1276 mL) under a nitrogen atmosphere, while maintaining the temperature in the range 15-22° C. The mixture is stirred for 4-7 hours until ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, is consumed, as determined by HPLC [Column: Zorbax Eclipse XDB-C8, 4.6.x.150 mm. Eluant: Acetonitrile/water; wavelength 225 nm. Retention times: potassium 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxylate, 1.3 min., ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, 6.4 min., ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate, 7.3 min., N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]-pyrazole-2-carboxamide, 2.7 min.] The slurry is filtered and the filter cake is washed with 2B ethanol (1800-2400 ml in portions). The wet cake is dried under vacuum at 60-65° C. to constant weight. Crude potassium 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxylate [426.3 g, 81percent (based on calcd. quantity of] is obtained as a tan, hygroscopic, solid, which is characterized using NMR, HPLC, KF and ash determinations. The cake may optionally be reslurried in 2B ethanol, if necessary, to remove impurities (such as potassium 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-3-carboxylic acid). The product of the example is used directly in the next step (see example 10). [TABLE-US-00002] Starting KOH/EtOH KOH/EtOH Reaction 2-Acid 2-Acid Crude esters Real Addition Addition Hold K Salt K Salt 2-Ester/3-Ester 2-Ester Time Temp Time Product percent yield (g) (g) (hours) ° C. (hours) (g) real to crude 587 275 1 20-25 4 249 85 1064 494 1 17-26 4 426 81 1967 948 1.5 16-18 4 816 81(a) 2700 1150 1.2 10-20 3 1039 86(a) (a)Reslurried with 4 volumes ethyl alcohol to remove residual impurities
48%
Stage #1: With sodium ethanolate In ethanol at 15 - 22℃; for 10 h;
Stage #2: With hydrogenchloride In water
Sodium ethoxide solution, in denaturated ethanol (21 wt percent, 12 ml, 38 mmol) is added to 6.9 g (38 mmol) of the crude mixture of esters, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate and ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate in 3A ethanol (containing 3, 7percent water, 15 ml) and the mixture is stirred for 10 hours under a nitrogen atmosphere at 15-22° C. Consumption of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, is monitored by HPLC [Prodigy ODS3 4.6.x.150 mm column, 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02percent trifluoroacetic acid, UV detection at 215 nm. Retention times under these conditions were: 2.6-2.7 min. for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer), 2.8-2.9 minutes for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the undesired, less polar isomer) and 0.86 minutes for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid]. The resulting mixture is evaporated under diminished pressure to a residue as a syrup. The syrup is mixed with ether (25 ml), and the resulting precipitate is collected on a filter. The hygroscopic filter cake is washed with diethyl ether (100 ml) and then dissolved in water (10 ml). The pH of the solution is adjusted to a value of 2 with 1N hydrochloric acid and the mixture extracted with ethyl acetate (3.x.25 ml). The combined organic extract is dried over magnesium sulfate and evaporated to give 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as an off-white solid (1.40 g, 48percent), m.p. 140-145° C., which is characterized by NMR, mass spectrum, elemental analysis, and HPLC (Prodigy ODS3 4.6.x.150 mm column, with a 20 min gradient from 95:5 to 30:70 using water/acetonitrile with 0.02percent trifluoroacetic acid and UV detection at 215 nm. The retention time for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid was 7.2 minutes) The product of the example is used directly in the next step (see example 13).
Reference: [1] Patent: US2004/242874, 2004, A1, . Location in patent: Page 14-15
[2] Patent: US2004/242874, 2004, A1, . Location in patent: Page 14
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 86477-09-0 ]

Esters

Chemical Structure| 5744-51-4

[ 5744-51-4 ]

Ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate

Similarity: 0.90

Chemical Structure| 115315-95-2

[ 115315-95-2 ]

Ethyl 1-phenyl-1H-pyrazole-3-carboxylate

Similarity: 0.82

Chemical Structure| 4027-57-0

[ 4027-57-0 ]

Ethyl 5-methylpyrazole-3-carboxylate

Similarity: 0.81

Chemical Structure| 802541-13-5

[ 802541-13-5 ]

Ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Similarity: 0.79

Chemical Structure| 25016-17-5

[ 25016-17-5 ]

Methyl 5-methyl-1H-pyrazole-3-carboxylate

Similarity: 0.78

Related Parent Nucleus of
[ 86477-09-0 ]

Other Aromatic Heterocycles

Chemical Structure| 796729-03-8

[ 796729-03-8 ]

5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

Similarity: 0.90

Chemical Structure| 307313-03-7

[ 307313-03-7 ]

4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid

Similarity: 0.86

Chemical Structure| 802541-13-5

[ 802541-13-5 ]

Ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate

Similarity: 0.79

Chemical Structure| 32286-99-0

[ 32286-99-0 ]

1-Methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

Similarity: 0.77

Chemical Structure| 951626-95-2

[ 951626-95-2 ]

Ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

Similarity: 0.77